A phase 2 controlled human infection trial has found that two doses of WRSs2, a live-attenuated oral vaccine candidate against Shigella sonnei, achieved 89% protection — the highest efficacy reported for any Shigella vaccine candidate — with no serious adverse events, advancing a century-long quest for a licensed vaccine against the diarrheal pathogen.
Researchers from Cincinnati Children's Hospital Medical Center and collaborating institutions have reported that WRSs2, a live-attenuated oral vaccine candidate against Shigella sonnei, achieved 89% protective efficacy in a phase 2 controlled human infection trial — the highest level of protection reported for any Shigella vaccine candidate to date.¹ The findings were published today in
Shigella is a group of highly contagious bacteria transmitted through contaminated food and water and via person-to-person contact. It is a leading cause of diarrheal disease and dysentery globally, estimated to cause up to 165 million infections and over 600,000 deaths annually — with children under five years old bearing the greatest burden, accounting for approximately 62 million cases.³ In the US alone, an estimated 450,000 Shigella infections occur each year, with over 5,000 hospitalizations.¹
Despite more than a century of research, no licensed Shigella vaccine currently exists. While strides have been made over the years to develop and commercialize effective vaccines for a wide range of infectious diseases, some illnesses remain particularly
The challenge is partly biological — Shigella comprises four major species and dozens of serotypes, each requiring serotype-specific immune protection — and partly logistical, as controlled efficacy trials in pediatric populations in endemic regions demand significant regulatory and infrastructure investment. Growing antimicrobial resistance has added urgency: Shigella is increasingly difficult to treat with standard antibiotics, and the WHO has designated it a priority pathogen for new countermeasures.² Vaccine development has focused on three approaches: live attenuated strains, killed whole-cell preparations, and conjugate subunit vaccines; but none has cleared the bar for licensure.⁴
WRSs2 is a live-attenuated S. sonnei vaccine candidate developed by the Walter Reed Army Institute of Research (WRAIR) and the Naval Medical Research Command with NIAID support, engineered through targeted deletions of the virG spreading gene and the senA/senB enterotoxin genes to reduce reactogenicity while preserving immunogenicity.⁵
"This study represents an important step forward in developing a safe and effective vaccine against Shigella. With continued research, we have the potential to significantly reduce the global burden of this disease, particularly among children."
— Robert Frenck, MD, Professor, Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center
The phase 2 randomized, double-blind, placebo-controlled trial enrolled 108 healthy adults aged 18 to 49 years between October 2022 and January 2024 (NCT04242264).⁶ Seventy-three participants completed the controlled infection challenge phase, in which vaccinated and placebo recipients were deliberately exposed to a virulent S. sonnei challenge strain to test vaccine protection.
Two doses of WRSs2 provided 89% protection against Shigella sonnei infection compared with placebo — substantially exceeding efficacy levels reported in prior Shigella vaccine trials.¹ Vaccinated participants also experienced significantly less severe symptoms and lower levels of bacterial shedding in stool, suggesting the vaccine may also reduce onward transmission — a meaningful secondary benefit given Shigella's low infectious dose and high transmissibility.¹ No vaccine-related serious adverse events were reported, and a small number of participants who experienced temporary side effects prompted dosing adjustments during the trial.¹
"This study represents an important step forward in developing a safe and effective vaccine against Shigella," said Robert Frenck, MD, professor in the Division of Infectious Diseases at Cincinnati Children's Hospital Medical Center and joint senior author of the study. "With continued research, we have the potential to significantly reduce the global burden of this disease, particularly among children."¹
The researchers emphasize that further optimization is needed before WRSs2 advances to licensure. Current priorities include confirming long-term durability of protection, identifying the optimal dosing regimen, and expanding evaluation to broader Shigella strain coverage — S. sonnei is most prevalent in higher-income countries, with outbreaks tied to travel, military deployments, and childcare settings, while S. flexneri dominates in lower-income endemic regions where pediatric mortality is highest.¹
WRSs2 is not yet commercially manufactured. Development has proceeded through a government-academic consortium involving WRAIR, NIAID, the Naval Medical Research Command, Emory University's Hope Clinic, the Emmes Company, and Cincinnati Children's — reflecting a public health-driven model common to enteric disease vaccine development, where commercial market incentives alone have historically been insufficient to drive licensure.¹
The data support advancing WRSs2 into larger efficacy trials in high-risk populations, including children in endemic settings, which would be required to support a regulatory submission.¹ Given the intersection with
The controlled human infection model used in this trial — in which healthy volunteers are intentionally exposed to a pathogen under clinical supervision after vaccination — is an increasingly recognized tool for accelerating enteric vaccine development, particularly for diseases where field efficacy trials in endemic populations are logistically demanding. The model allows efficacy signals to be detected with relatively small sample sizes and compressed timelines, with challenge outcomes serving as a regulatory-accepted early indicator of vaccine performance. As noted in a recent BioPharm International panel on
